Project Summary Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting nearly 1% of adults that causes a painful, destructive inflammatory arthritis with long-term serious consequences including chronic pain, disability, accumulation of morbidities, and excess mortality. Cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) are elevated in the serum of two-thirds of RA patients. Seropositive RA patients are more likely to develop serious respiratory outcomes including interstitial lung disease and chronic obstructive pulmonary disease (COPD). Patients with seropositive RA have 3-fold excess respiratory mortality compared to the general population. Lung involvement is known to be an important contributor to excess RA morbidity and mortality, however less is known about its role in RA risk. Previous studies suggest that mucosal surfaces of the lung may be an initiating site, after smoking or exposure to other inhalants, where CCP and RF may be formed years before joint symptoms first develop. Therefore, patients with respiratory diseases such as asthma and COPD may be more likely to develop RA. These investigations will study whether individuals with respiratory diseases are more likely to develop RA. In the first aim, we will perform a prospective cohort study within the Nurses? Health Studies, two longitudinal studies with up to 40 years of follow-up where we have we have already identified women who developed RA and collected data including RA serologic status. We will investigate whether women with asthma or COPD are more likely to develop RA overall, and by serologic status, compared to women without these diseases while adjusting for important confounders or mediators such as smoking. In the second aim, we will perform a case- control study in the Partners Biobank and replicated in the Nurses? Health Studies to test whether genetic factors related to respiratory diseases and function are related to RA risk. The Partners Biobank is a large research repository recruited from patients seen at Brigham and Women?s Hospital, Massachusetts General Hospital, and affiliated satellite clinics in Boston, Massachusetts. We will analyze genotype data that has already been collected in the Partners Biobank and the Nurses? Health Studies. Dr. Jeffrey Sparks (the PI) is an Assistant Professor of Medicine at Brigham and Women?s Hospital and Harvard Medical School. He has made significant progress in his ongoing K23 studies funded by NIAMS that are investigating RA-specific factors and subsequent respiratory outcomes. These proposed studies will complement those findings by using RA as the outcome instead of the exposure thereby describing a bi- directional association between respiratory diseases and RA. These will be secondary analyses of data already collected in datasets that the PI has access to and familiarity with analyzing. Together, the results of these studies will provide strong preliminary data supporting an R01 application to further investigate the effect of RA-related autoantibodies on respiratory function, structure, and outcomes.